James J. Douglas*, David Buttar, Katharine Locke and Andrew Turner,
{"title":"An Intramolecular Diels–Alder Approach to the Isoindolinone Core of AZD8154","authors":"James J. Douglas*, David Buttar, Katharine Locke and Andrew Turner, ","doi":"10.1021/acs.oprd.3c00507","DOIUrl":null,"url":null,"abstract":"<p >A new route to the isoindolinone core of dual phosphoinositide 3-kinases-γδ inhibitor AZD8154 was required to enable multikilogram supply during development toward first in human (FIH) trials and beyond. Aiming to avoid a problematic benzyl bromide intermediate encountered in the medicinal chemistry synthesis, we report a proof-of-concept convergent route featuring a key intramolecular Diels–Alder aromatization sequence. Critical to the success of this approach was the identification of <sup>t</sup>BuOK-mediated aromatization conditions, reliant upon an electron-withdrawing sulfone moiety installed at an early stage. More conventional protic acid dehydration/aromatization conditions were unsuccessful, and using the Lewis acid BF<sub>3</sub>·Et<sub>2</sub>O gave an unexpected sulfone rearrangement product. Overall, the new route proceeded in 38% yield (four-step longest linear sequence) in <10 total steps and was considered viable for further optimization and scale-up.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 6","pages":"2284–2295"},"PeriodicalIF":3.1000,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Organic Process Research & Development","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.oprd.3c00507","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
引用次数: 0
Abstract
A new route to the isoindolinone core of dual phosphoinositide 3-kinases-γδ inhibitor AZD8154 was required to enable multikilogram supply during development toward first in human (FIH) trials and beyond. Aiming to avoid a problematic benzyl bromide intermediate encountered in the medicinal chemistry synthesis, we report a proof-of-concept convergent route featuring a key intramolecular Diels–Alder aromatization sequence. Critical to the success of this approach was the identification of tBuOK-mediated aromatization conditions, reliant upon an electron-withdrawing sulfone moiety installed at an early stage. More conventional protic acid dehydration/aromatization conditions were unsuccessful, and using the Lewis acid BF3·Et2O gave an unexpected sulfone rearrangement product. Overall, the new route proceeded in 38% yield (four-step longest linear sequence) in <10 total steps and was considered viable for further optimization and scale-up.
期刊介绍：
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.
京公网安备 11010802042870号
京ICP备2023020795号-1
分享
求助内容：
应助结果提醒方式：
扫码关注我们
